The objective of this proposal is to determine the function of the insulin-like growth factor I receptor (IGF IR) in the control of vascular smooth muscle cell (VSMC) growth responses in vivo. The proliferation of VSMC is a characteristic event in a number of pathologic conditions, particularly hypertension, restenosis, and atherosclerosis. A variety of growth factors are involved in this growth response and include insulin-like growth factor I (IGF I), fibroblast growth factor, platelet-derived growth factor, angiotensinII, and thrombin. Of note, it appears that activation of the IGF I-IGF IR pathway is a critical and essential event for VSMC proliferation in response to growth factors. There is evidence that an activated IGF IR receptor is a requirement for growth factor-induced mitogenesis. This proposal will test the hypothesis that the IGF IR is a major mediator of VSMC growth responses by targeting the IGF IR in vivo. Using the rat model of carotid arterial injury and adenovirus-mediated gene transfer, VSMC will be locally transfected with expression vectors generating an antisense IGF IR RNA or a truncated, tyrosine- kinase deficient IGF IR. Transfection with the antisense expression construct has resulted in marked inhibition of growth in vitro, and the kinase-deficient IGF IR is expected to function as a dominant negative mutant It is anticipated that neointimal accumulation following balloon injury will be inhibited, thus establishing a major role for the IGF IR in mediating VSMC proliferation in vivo.